Peter M. Corry

RTOG quality assurance guidelines for clinical trials using hyperthermia.

M. W. DEWHIRST, D.V.M., PH.D.,* T. L. PHILLIPS, M.D.,+ T. V. SAMULSKI, PH.D.,+ P. STAUFFER, MSEE,? P. SHRIVASTAVA, PH.D.,+ B. PALIWAL, PH.D.,+ T. PAJAK, PH.D.,+ M. GILLIM, PH.D.,+ M. SAPOZINK, M.D., PH.D.,+ R. MYERSON, M.D., PH.D.,+ F. M. WATERMAN, PH.D.,+ S. A. SAPARETO, PH.D.,+ P. CORRY, PH.D.,+ T. C. CETAS, PH.D.,+ D. B. LEEPER, PH.D.,+ P. FESSENDEN, PH.D.,+ D. KAPP, M.D., PH.D.,+ J. R. OLESON, M.D., PH.D.+ AND B. EMAMI, M.D.*

Human Cancer Treatment with Ultrasound

Absmct-Despite the interest in hyperthermia and the rather significant advantages that ultrasound possesses over other methods for localized heating, there remain only a few reports of human studies with welldocumented thermal dosimetry that permit the evaluation of the antitumor efficacy of ultrasound treatment. In this paper, these reports are discussed, and the biological basis for the application of ultrasound hyperthermia as an antitumor modality is presented. Further, clinical results involving the application of ultrasonic hyperthermia alone, and in conjuction with chemotherapy and radiation in 215 patients are reported. Overall objective response rates for ultrasoundalone,ultrasound with chemotherapy, and ultrasound with radiation therapy were 45 percent, 60 percent, and 66 percent, respectively. Of particular encouragement was the treatment of advanced primary breast cancer with ultrasoundcombined withchemotherapy, wherethe first seven wesexhibited a 100 percent overall response rate to therapy.

Noninvasive visualization of tumors in rodent dorsal skin window chambers

A novel model for evaluating anti-cancer therapies.

Cytotoxic Effects of Ultrasound in Vitro Dependence on Gas Content, Frequency, Radical Scavengers, and Attachment

CHO cells were exposed to therapeutic-intensity ultrasound under various conditions. Cell killing was dependent upon the amount of gas dissolved in the treatment medium. No decrease in survival was observed at 2.40 and 3.40 MHz under conditions which had produced killing at 1.70, 1.07, and 0.82 MHz. Cell death occurred primarily within 15 min of exposure and probably involved membrane damage. One radical scavenger, cysteamine, completely protected the cells from ultrasound-induced damage whereas another, cystamine, did not. Attachment of the cells to a Mylar membrane also protected them from damage. Under conditions most closely resembling in vivo ultrasound exposures no decrease in survival was observed for intensities as great as 14 W/cm2 and 30-min duration. The cell killing observed was apparently due to cavitation and may have involved formation of intracellular radicals. Although the role of radicals is not unequivocally demonstrated, a better understanding of the mechanisms of ultrasound-induced damage is needed before this modality can be considered to be without

Equivalence of continuous and pulse simulated low dose rate irradiation in 9L gliosarcoma cells at 37° and 41°C

Abstract The development of a brachytherapy technique that will use a scanning source to simulate continuous low dose rate irradiation holds the possibility of improving dose distributions and other clinically relevant factors as well as enhancing radiation safety. Rat 9L gliosarcoma cells growing in vitro have been used as a model to determine the role of fraction size when individual pulses of irradiation are given at appropriate intervals to result in an overall dose rate that is identical to currently applied continuous low dose rate irradiation. With an overall dose rate of 0.5 Gy/hr, cell killing was identical for fractionation schemes of 0.25 Gy every 0.5 hr, 1.00 Gy every 2.0 hr, and 3.00 Gy every 6.0 hr. The cell sensitivity of these schemes was also identical to continuous irradiation at the same overall dose rate. Increasing the fraction size to 6.0 Gy with intervals of 12 hr increased the cytotoxicity. This breaking point was above the D q (3.9 Gy) of acutely irradiated 9L cells. These data support the hypothesis that continuous low dose rate irradiation can be simulated by fractionated high dose rate irradiation as long as the fraction size remains less than the D q of the acute radiation response of the cells and the overall dose rate remains constant. The role of simultaneous heating at 41°C during pulsed and continuous low dose rate irradiation was also investigated. Substantial sensitization was observed for both continuous low dose rate irradiation and pulse simulated low dose rate irradiation. The D o thermal enhancement ratios were 1.98 and 1.92, respectively. The above results demonstrate that modalities utilizing intermittent high dose rate irradiation can be designed such that they will be equivalent to continuous low dose rate irradiation, and that in either case simultaneous extended low temperature heating can greatly enhance the cytotoxic effects of these irradiations.

Hypoxia-induced bFGF gene expression is mediated through the JNK signal transduction pathway.

Although the synthesis of angiogenic factors in hypoxic regions of solid tumors is recognized as one of the critical steps in tumor growth and metastasis, the signal transduction pathway involved in hypoxic induction of basic fibroblast growth factor (bFGF) gene expression is still obscure. In the study described here, we investigated the intracellular responses to hypoxia and the mechanisms triggering the initiation of angiogenic activity in drug-resistant human breast carcinoma MCF-7/ADR cells. Northern blots showed an increase in the level of c-jun, c-fos, and bFGF mRNA during hypoxia. Gel mobility-shift analysis of nuclear extracts from hypoxia-exposed cells showed an increase in AP-1 binding activity. In addition, hypoxic treatment strongly activated c-Jun N-terminal kinase 1 (JNK1), leading to phosphorylation and activation of c-Jun. Expression of a dominant negative mutant of JNK1 suppressed hypoxia-induced JNK1 activation as well as bFGF gene expression. Taken together, hypoxia-induced bFGF gene expression is mediated through the stress-activated protein kinase (SAPK) signal transduction pathway.

Effect of Ionizing Radiation on AP-1 Binding Activity and Basic Fibroblast Growth Factor Gene Expression in Drug-sensitive Human Breast Carcinoma MCF-7 and Multidrug-resistant MCF-7/ADR Cells

We studied the effect of ionizing radiation on the activation of the AP-1 transcription factors and the regulation of basic fibroblast growth factor (bFGF) gene expression in drug-sensitive human breast carcinoma (MCF-7) cells and its drug-resistant variant (MCF-7/ADR) cells. Northern blot and gel mobility shift assays showed that 135 cGy of ionizing radiation induced c-jun and c-fos gene expression, AP-1 binding activity, as well as bFGF gene expression in MCF-7/ADR cells. In MCF-7 cells, however, we observed little/no induction of bFGF gene expression and AP-1 binding activity after the stress. Nevertheless, MCF-7 cells transfected with plasmids containing c-jun gene contain high levels of bFGF protein. H-7 (60 μg/ml), a potent protein kinase C (PKC) inhibitor, inhibited the stress-induced AP-1 binding activity and bFGF gene expression in MCF-7/ADR cells. Corroborating this observation, overexpression of PKCα induced bFGF gene expression in MCF-7 cells. Taken together, these results suggest that stress-induced bFGF gene expression is mediated through the activation of PKC and AP-1 transcription factors. Differences in the levels of PKC activity and AP-1 binding factors may be responsible for differential expression of bFGF among breast cancer cell lines. Although there are large differences in response to ionizing radiation between MCF-7 and MCF-7/ADR cell lines, we observed no significant differences in radiocytotoxicity between them.

Lack of radiosensitization after paclitaxel treatment of three human carcinoma cell lines

Background. Several recent studies have suggested radiosensitizing effects of paclitaxel, a microtubular inhibitor. To test the universality of this finding, the interaction between paclitaxel and radiation treatment of cell lines derived from three common human carcinomas MCF‐7 (breast cancer); DUT‐145 (prostate cancer); and HT‐29 (colon cancer) was evaluated. The study focused on the ability of paclitaxel to block cells at the G2‐M phase of the cell cycle and potentially enhance the radiation sensitivity of the cells.

RTOG quality assurance guidelines for interstitial hyperthermia

This document specifies the current recommendations for quality assurance for hyperthermia administration with interstitial techniques as specified by the Radiation Therapy Oncology Group (RTOG). The document begins by providing a brief description of the physical principles behind the use of the three most commonly used methods of interstitial hyperthermia: radiofrequency (RF-LCF), microwave antennas, and ferromagnetic seeds. Emphasis is placed on features that effect quality assurance. Specific recommendations are provided for: a) Pretreatment planning and equipment performance checks, b) Implant considerations and documentation, c) Thermometry, and d) Safety procedures. Specific details regarding quality assurance issues that are common to all local and regional hyperthermia methods are outlined in previous documents sponsored by the RTOG. It is anticipated that technological advances may lead to future modifications of this document.

Application of the time-dependent Green's function and Fourier transforms to the solution of the bioheat equation.

A theory for solving the bioheat equation is developed using a time-dependent Greens function and Fourier transform techniques. The description of both steady-state and time-dependent data are placed into a single framework which can also describe the effects of inhomogeneous blood perfusion. The theory is illustrated by examples including the modelling of a thermal conduction hyperthermia system and a new RF interstitial system. A possibility for measuring the blood perfusion parameter and thermal conductivity from the steady state temperature distribution of a point source is also proposed.